Abstract
The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P1-5). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P1 and S1P3 receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.
Original language | English |
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Pages (from-to) | 663-677 |
Number of pages | 15 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 15 |
Issue number | 2 |
DOIs | |
State | Published - 15 Jan 2007 |
Externally published | Yes |
Keywords
- FTY720
- Immune-modulation
- Sphingosine 1-phosphate
- VPC23019
- VPC44116